One pharmaceutical composition widely known to the prior art as an antibacterial agent of the nitrofuran series is 1-(5'-nitrofurfurylideneamino)-hydantoin having the following structural formula ##STR1## and trade named as Nitrofurantoin and Furadantin.
Said pharmaceutical composition is quickly absorbable from the gastrointestinal tract, with the drug concentration in the blood and in the urine capable of reaching a level sufficient to produce a therapeutic effect.
Said pharmaceutical composition is easy to use in medical practice under conditions of both hospital and outpatient treatment, considering that it is designed for oral administration (as capsules, tablets, or suspension).
However, said pharmaceutical composition has a relatively limited spectrum of action, being used in practical medicine for the theory of infectious urologic diseases only.
Also, said pharmaceutical composition is noticeably toxic. In the case of oral administration to white mice, LD.sub.50 is 166.7 mg/kg.
Sometimes this pharmaceutical composition is observed to meet with intolerance.
The bacteriostatic concentration value for this pharmaceutical composition is comparatively high, and this, coupled with the considerable level of toxicity of the drug, will frequently restrict its usage in medical practice.
Besides, said pharmaceutical composition is quickly removed from the organism.
Another pharmaceutical composition widely known in the prior art as an antibacterial agent of the nitrofuran series is N-[.beta.-(5'-nitrofuryl-2')-acrylidene]-1-aminohydantoin having the following structural formula: ##STR2## and commercialized under the trade name of Furagin.
This pharmaceutical composition possesses a wider spectrum of therapeutic action than the aforesaid Nitrofurantoin and Furadantin. Apart from being used for the treatment of infectious urologic diseases, it can be utilized, in particular, as an antibacterial agent for the treatment of wounds and purulent infections.
With oral administration of said pharmaceutical composition, the drug concentration in the urine will reach a level sufficient to give a therapeutic effect.
The bacteriostatic concentration of Furagin for various aspects of pathogenic microorganisms is 10 to 20 times lower than the respective value for Nitrofurantoin.
Besides, said pharmaceutical composition is less toxic than Nitrofurantoin or Furadantin.
However Furagin is but very poorly soluble in water. This puts a limitation on its use by injection and, in particular, by intravenous administration, as also on its being used, as ampouled solution, for treating operating fields.
Also, in quite a number of cases, said pharmaceutical composition is observed to meet with intolerance.
A further pharmaceutical composition known to the prior art as an antibacterial agent of the nitrofuran series is potassium salt of N-[.beta.-(5'-nitrofuryl-2')-acrylidene]-1-aminohydantoin having the following structural formula ##STR3## and commercialized under the trade name of Solafur (see U.K. Pat. No. 1,129,195).
Solafar is an antibacterial agent of a broader spectrum of action compared to Furagin. The drug retains its activity with reference to such pathogenic strains of staphylococci and a number of such microorganisms as are resistant to other chemotherapeutic agents and antibiotics. Also, microorganisms will develop practically no drug resistance to Solafur. One characteristic feature of said pharmaceutical composition is its capability of producing synergistic action with a range of antibiotics upon most pathogenic microorganisms.
Solubility of Solafur in water is higher than that of the aforementioned Furagin, and this favours its administration by injection and its use for treating operating fields.
Said pharmaceutical composition is used in medical practice as 0.1% isotonic solution administered by injection and, specifically, by intravenous injection.
However, when the desired drug concentration in the blood is higher than the bacteriostatic value, the Solafur solution is to be administered intravenously by the drop method and in large quantities.
A faster method of administration used with this drug will cause headache and nausea.
Besides, in some cases this pharmaceutical composition is observed to meet with intolerance.
Administration of pharmaceutical compositions by injection and, more particularly, by intravenous injection, puts certain limitations on their use in the treatment of outpatients.
The instability in storage characteristic of aqueous solutions of Solafur makes it necessary to prepare solutious ex tempore, immediately before use.
In the case of oral administration to white mice, LD.sub.50 of Solafur amounts to 390 mg/kg.
Considering the fact that Furagin is an acid (pK=6) and is capable of forming salts, administration of its potassium salt, i.e. Solafur, by injection has been deemed unsuitable by those skilled in the art, inasmuch as, the pH inside the stomach being generally within 1 to 3, those skilled in the art were of the opinion that the effect of the acid environment of the stomach would be to convert Solafur to the parent Furagin whose action would actually determine the therapeutic effect of the pharmaceutical composition used.
Investigations carried out on excretions of Furagin and Solafur following oral adminstration to rabbits weighing 2.8 to 3.5 kg of said pharmaceutical compositions in 5 mg/kg dosages, have demonstrated that over the first 4 hours after administration the concentrations of said compounds in the urine are roughly equal. The total quantity of Furagin removed over a period of 48 hours amounts to 2.75.+-.0.41% of the total quantity of the pharmaceutical composition administered. For Solafur, respectively, this quantity is equal to 2.83.+-.0.48% of the total quantity of Solafur administered.
In view of the reasons stated above, Solafur is used in medical practice for injections only.